Genetic Studies of Alzheimer's Disease in Jewish and Arab Populations

犹太人和阿拉伯人群阿尔茨海默病的遗传学研究

• 批准号: 10639024
• 负责人: Lindsay A. Farrer
• 金额: $ 238.97万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639024
• 关键词: Admixture; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Arabs; Ashkenazim; Bioinformatics; Biological Markers; Blood; Blood specimen; Brain; Caucasians; Clinical; Clinical Trials; Cognitive; Coupled; DNA; Data; Data Set; Development; Drug Targeting; Environmental Exposure; Environmental Risk Factor; Ethnic Origin; Ethnic Population; European ancestry; Evaluation; Funding; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Diseases; Genetic Drift; Genetic Transcription; Genetic study; Genotype; Goals; Haplotypes; Human; Individual; Israel; Jews; Joints; Lead; Life Style; Light; Location; Measures; Medical History; Mendelian randomization; Methods; Middle East; Modeling; Modification; Mutation; Northern Africa; Nucleotides; Outcome; Participant; Pathogenicity; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Process; Proteins; Quantitative Trait Loci; Risk; Risk Assessment; Role; Sampling; Satellite Viruses; Sequence Alignment; Site; Spain; Specimen; Tissues; United States National Institutes of Health; Variant; Virus; admixture mapping; analytical method; ancestry analysis; apolipoprotein E-4; brain magnetic resonance imaging; clinical examination; cognitive testing; cohort; drug development; follower of religion Jewish; gene network; genetic analysis; genetic architecture; genetic testing; genome sequencing; genome wide association study; genome-wide; insertion/deletion mutation; machine learning method; neurofilament; next generation sequencing; novel; patient registry; phenotypic data; pleiotropism; positional cloning; prospective; protein structure; recruit; risk variant; tau Proteins; tau-1; trait; viral DNA; viral detection; whole genome

Most discoveries of the genetic basis of Alzheimer disease (AD) were made in Caucasians of European ancestry (EAs) and required samples between 10,000 and 150,000 subjects to detect them. We and others have demonstrated that discovery of AD risk variants can be accomplished in more genetically homogeneous cohorts comprising several thousand or fewer subjects. Studies of non-EA populations also afford the opportunity to discover variants that are relatively rare or absent in EAs and that display a smaller effect size in EAs due to modification by other genes and environmental factors. We will focus on Jews and Arabs currently living in Israel who are descended from the Middle East and North Africa (MENA). Although MENA Jews assimilated to some extent with their non-Jewish neighbors, they have maintained a distinctive genetic profile that reflects some admixture with non-Jews, ancient Jewish background, and a unique component reflecting genetic drift and new mutations during the last two millennia. Our previous studies of Arabs living in the Israeli village called Wadi Ara revealed a genome-wide significant association for AD with ACE, were central to the establishment of SORL1 as an AD gene, and contributed to a trans-ethnic GWAS leading to the discovery of several novel AD genes. In this project, we will leverage the genetic architecture of MENA Jews and Israeli-Arabs, as well as their distinctive environmental exposures and lifestyles, to promote discovery of AD-related genes and variants. Specifically, we will recruit 3,000 MENA Jews at three sites in Israel, as well as 1,000 Israeli-Arabs located in multiple villages (equal numbers of AD cases and controls in the total sample). We will obtain from each participant a blood specimen for DNA and biomarker studies, and phenotypic data including clinical, cognitive test, medical history and lifestyle information, as well as brain MRI data for a portion of the sample. DNA specimens will be whole genome sequenced (WGS). WGS data will be processed using pipelines established by the Alzheimer Disease Sequencing Project (ADSP). We will conduct a GWAS for AD using admixture mapping and methods for single variant and gene-based tests. Top-findings will be replicated in Ashkenazi Jewish and non-Jewish datasets assembled by the Alzheimer Disease Genetics Consortium and ADSP using trans-ethnic analysis and approaches that focus on variants affecting protein structure, transcription, and gene expression. We will also conduct GWAS for age at onset and AD biomarkers using single outcome and pleiotropy models. Next, we will identify gene targets of the top-ranked SNPs by performing expression quantitative trait locus analysis using locally derived and publicly available data containing genotype and gene expression data in brain and other tissues, and establish functional connections among the top-ranked SNPs and genes using pathway, co- expression network, and Mendelian randomization analysis. Finally, we will evaluate the association of viruses detected in WGS data with AD using machine learning methods and regression models. We expect that this project will identify novel targets for development of effective drugs to treat or retard processes leading to AD.

大多数阿尔茨海默病 (AD) 遗传基础的发现都是在欧洲血统的白种人中发现的 （EA）并需要 10,000 至 150,000 名受试者的样本来检测它们。我们和其他人有 证明 AD 风险变异的发现可以在基因更加同质的队列中完成 包括数千个或更少的主题。对非 EA 人群的研究也提供了机会 发现 EA 中相对罕见或不存在的变体，并且由于以下原因在 EA 中显示较小的效应量 其他基因和环境因素的改变。我们将重点关注目前居住在以色列的犹太人和阿拉伯人 他们是中东和北非 (MENA) 的后裔。尽管中东和北非地区的犹太人已被一些人同化 与他们的非犹太邻居相比，他们保持着独特的遗传特征，反映了一些 与非犹太人、古代犹太背景的混合，以及反映遗传漂变和新事物的独特成分 过去两千年的突变。我们之前对居住在以色列瓦迪阿拉村的阿拉伯人的研究 揭示了 AD 与 ACE 在全基因组范围内的显着关联，是 SORL1 建立的核心 作为 AD 基因，并促成了跨种族 GWAS，导致发现了几个新的 AD 基因。在 在这个项目中，我们将利用中东和北非犹太人和以色列阿拉伯人的遗传结构，以及他们独特的 环境暴露和生活方式，以促进 AD 相关基因和变异的发现。具体来说，我们 将在以色列的三个地点招募 3,000 名中东和北非犹太人，以及位于多个村庄的 1,000 名以色列阿拉伯人 （总样本中 AD 病例和对照的数量相同）。我们将从每个参与者身上获取血液 用于 DNA 和生物标志物研究的样本，以及包括临床、认知测试、病史在内的表型数据 和生活方式信息，以及部分样本的脑部 MRI 数据。 DNA 样本将是完整的 基因组测序（WGS）。 WGS 数据将使用阿尔茨海默病建立的管道进行处理 测序项目（ADSP）。我们将使用混合映射和单一方法进行 AD 的 GWAS 基于变异和基因的测试。顶级发现将在德系犹太人和非犹太人数据集中复制 由阿尔茨海默病遗传学联盟和 ADSP 使用跨种族分析和 专注于影响蛋白质结构、转录和基因表达的变异的方法。我们还将 使用单一结果和多效性模型对发病年龄和 AD 生物标志物进行 GWAS。接下来，我们将 通过使用以下方法进行表达数量性状基因座分析来识别排名靠前的 SNP 的基因靶标 本地衍生的和公开的数据包含大脑和其他部位的基因型和基因表达数据 组织，并使用途径、共-在排名靠前的 SNP 和基因之间建立功能连接 表达网络和孟德尔随机化分析。最后，我们将评估病毒的关联性 使用机器学习方法和回归模型在 AD 的 WGS 数据中检测到。我们期望这 该项目将确定开发有效药物的新目标，以治疗或延缓导致AD的过程。